Poster Presentation

Depolarization-induced suppression of inhibition (DSI) is known to be mediated by
the endocannabinoid 2-arachidonoylglycerol (2-AG). It's calcium-dependent production
and subsequent retrograde diffusion from postsynaptic pyramidal cells to presynaptic
cannabinoid receptors (CB1) located on the preterminal axon and the perisynapse of CCK-containing basket cells
in the CA1 region of the hippocampus transiently suppresses GABA transmitter release
[1,3]. This endocannabinoid signaling system has many physiological implications for memory-related
synaptic plasticity and gamma oscillations; exogenous application of synthetic cannabinoids
has a dramatic impact on the functioning of this system, more precisely the loss of
synchronized cell assemblies by modification of inhibitory feedback loops in the CA1
region of the hippocampus [4,5], thus altering outcome of spatial memory-related tasks in animals and learning in
humans.

This study uses computational modeling methods to understand the modes of production
and action of the endocannabinoid 2-AG in monosynaptically suppressing transmitter
release. Using the NEURON simulation environment [2], we developed an isopotential model cell with an L-type Ca2+ channel being the sole pathway for Ca2+ entry required for synthesis of 2-AG. The observed time courses for 2-AG passive
diffusion (between adjacent shell compartments), and uptake and intracellular hydrolysis
can be observed with successive depolarizing current pulses delivered by a single-electrode
voltage clamp. These changes in concentration levels in the compartment representing
the perisynapse and preterminal axon (the CCK-positive basket area covering the pyramidal
cell expressing CB1) are directly proportional to the GABA synaptic depression due to inhibition of presynaptic
calcium channels. The amount of CB1 activation is described by the Langmuir equation and, together with the Ca2+ ion cooperativity for transmitter release, affects the synaptic conductance profile
described by the solution of two coupled linear ODEs. It is shown that in the model,
[Ca2+]i had to rise to 0.1μM in order to sufficiently activate the kinetic model describing
the Phospholipase C-Diacylglycerol pathway (PLC-DAG) for 2-AG production [1,3]. We also show highly simplified dynamics of PLC after stimulation by [Ca2+]i , DAG production, and the spatial gradient in 2-AG across compartments (discretization
of Fick's second law for diffusion). Uptake and intracellular hydrolysis is driven
by the concentration gradient and the association rate constant for the irreversible
reaction hydrolysing 2-AG. The end result observed is the recovery of biexponential
postsynaptic conductance time course, which can vary depending on as yet unknown parameter
values. The suppression can be effective over a much smaller timescale due to summation
of high-frequency inputs by the synapse.

Acknowledgements

We would like to thank Ted Carnevale for helpful comments and suggestions during the
development of the model.